RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia.
To study the oncogenic role of the NRAS oncogene (NRAS(G12V)) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRE-NRAS(G12V) transgene system in Mll-AF9 knock-in mice developing AML. Conditional repression of NRAS(G12V) expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After marked decrease of AML blast cells, myeloproliferative disease (MPD)-like AML relapsed characterized by cells that did not express NRAS(G12V). In comparison with primary AML, the MPD-like AML showed significantly reduced aggressiveness, reduced myelosuppression, and a more differentiated phenotype. We conclude that, in AML induced by an Mll-AF9 transgene, NRAS(G12V) expression contributes to acute leukemia maintenance by suppressing apoptosis and reducing differentiation of leukemia cells. Moreover, NRAS(G12V) oncogene has a cell nonautonomous role in suppressing erythropoiesis that results in the MPD-like AML show significantly reduced ability to induce anemia. Our results imply that targeting NRAS or RAS oncogene-activated pathways is a good therapeutic strategy for AML and attenuating aggressiveness of relapsed AML.
Kim
Won-Il
WI
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, USA.
Matise
Ilze
I
Diers
Miechaleen D
MD
Largaespada
David A
DA
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D007958:Leukocyte Count; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D012008:Recurrence
C489902:Mllt3 protein, mouse; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D016283:Proto-Oncogene Proteins p21(ras)